Hepatitis B Virus (HBV) infection is a major public health problem worldwide, responsible for significant morbidity and mortality from chronic liver disease. It is estimated that there are 350-400 million HBV carriers globally. 75% of chronic HBV patients live in Asia, and approximately 1.5 million people are infected in the United States. Also, despite the availability of effective vaccines, about 50,000-100,000 new cases are reported annually in the United States. The infection is more common in certain risk groups like men who have sex with men, renal dialysis patients and persons with haemophilia, Chronic hepatitis B affects 10-15% of first generation Asian Americans and approximately 5% of children adopted from Russia, Asia and Eastern Europe have chronic hepatitis. Chronic HBV also leads to severe liver diseases including cirrhosis and liver cancer (Hepatocellular Carcinoma), causing more than one million deaths per year.
The treatment for this large reservoir of chronically infected subjects is problematic, since existing drugs suppress but do not eliminate HBV. These drugs have a limited ability in controlling the virus and cause several side effects resulting in the premature discontinuation of their use by many HBV patients.
Clearance of infected hepatocytes requires the presence of virus-specific T cells which are able to secrete anti-viral cytokines. However, these virus-specific T cells are functionally impaired in chronic HBV infected patients. The defect of HBV-specific T cell immunity in these patients is thought to be the reason why a majority of patients experience HBV relapse when therapy is stopped.
80% of Hepatocellular Carcinoma (HCC) is associated with chronic HBV infection, making the 350 million people chronically infected with HBV the largest population at risk for developing HCC. HCC that develops in chronic HBV patients frequently possesses portions of the HBV genome integrated into the tumour cell chromosome resulting in the tumours expressing the viral antigen. Thus HBV antigens can be expressed on HCC cells. Cells infected by these viruses are recognized by the human immune system since the cells expose small peptides derived from the viral proteins in association with Major Histocompatibility complex (MHC)-class 1 molecules on their surface.
TCR-like monoclonal antibodies have been already produced using standard hybridoma approach or by employing phage antibody libraries. However, these antibodies have low binding affinities to their corresponding antigens be it HBV or tumour associated antigens.